Codesigning training for health providers to improve detection and response to elder abuse.

Background And Objectives: Screening for elder abuse can improve detection, but many health providers lack the necessary skills and confidence. To address this, training for health providers on elder abuse screening was co-designed as part of a trial aimed at improving elder abuse detection and response.

Research Design And Methods: Between March and April 2023, 7 health providers and 10 older people and family carers participated in two national Australian online codesign workshops.

Using neural biomarkers to personalize dosing of vagus nerve stimulation.

Background: Vagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. Achieving a better understanding of the relationship between VNS parameters and neural and physiological responses is therefore necessary to enable the design of personalized dosing procedures and improve precision and efficacy of VNS therapies.

The impact of elder abuse training on subacute health providers and older adults: study protocol for a randomized control trial.

Background: Elder abuse often goes unreported and undetected. Older people may be ashamed, fearful, or otherwise reticent to disclose abuse, and many health providers are not confident in asking about it. In the No More Shame study, we will evaluate a co-designed, multi-component intervention that aims to improve health providers' recognition, response, and referral of elder abuse.

Online Bayesian optimization of vagus nerve stimulation.

In bioelectronic medicine, neuromodulation therapies induce neural signals to the brain or organs, modifying their function. Stimulation devices capable of triggering exogenous neural signals using electrical waveforms require a complex and multi-dimensional parameter space to control such waveforms. Determining the best combination of parameters (waveform optimization or dosing) for treating a particular patient's illness is therefore challenging.

Oxidized Phospholipid oxPAPC Alters Regulatory T-Cell Differentiation and Decreases Their Protective Function in Atherosclerosis in Mice.

Background: Regulatory T cells (T) are protective in atherosclerosis but reduced during disease progression due to cell death and loss of stability. However, the mechanisms of T dysfunction remain unknown. Oxidized phospholipids are abundant in atherosclerosis and can activate innate immune cells, but little is known regarding their impact on T cells.

Solitary jejunal diverticulum: a rare unexpected cause of chronic pneumoperitoneum.

Jejunal diverticula are a rare acquired herniation of the mucosa and submucosa through the muscularis propria. They are asymptomatic in the majority of cases; however, they can present with non-specific abdominal symptoms and rarely complicate leading to acute abdomen. Perforation usually results in symptoms and signs of acute peritonitis and it is not an identifiable aetiology of chronic pneumoperitoneum.

GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis.

Adaptive changes in lysosomal capacity are driven by the transcription factors TFEB and TFE3 in response to increased autophagic flux and endolysosomal stress, yet the molecular details of their activation are unclear. LC3 and GABARAP members of the ATG8 protein family are required for selective autophagy and sensing perturbation within the endolysosomal system. Here, we show that during the conjugation of ATG8 to single membranes (CASM), Parkin-dependent mitophagy, and -induced xenophagy, the membrane conjugation of GABARAP, but not LC3, is required for activation of TFEB/TFE3 to control lysosomal capacity.

The latest in systemic lupus erythematosus-accelerated atherosclerosis: related mechanisms inform assessment and therapy.

Purpose Of Review: Accelerated atherosclerosis is a significant comorbidity and the leading cause of death for patients with systemic lupus erythematosus (SLE). It is now apparent that SLE-accelerated atherosclerosis is not driven solely by traditional cardiovascular risk factors, adding complexity to disease characterization and mechanistic understanding. In this review, we will summarize new insights into SLE-accelerated atherosclerosis evaluation, treatment, and mechanism.

Chromosome-Level Alpaca Reference Genome Improves Genomic Insight Into the Biology of New World Camelids.

The development of high-quality chromosomally assigned reference genomes constitutes a key feature for understanding genome architecture of a species and is critical for the discovery of the genetic blueprints of traits of biological significance. South American camelids serve people in extreme environments and are important fiber and companion animals worldwide. Despite this, the alpaca reference genome lags far behind those available for other domestic species.

Design and Discovery of -(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic.

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe (LXH254, Aversa, R.; et al.

Design and synthesis of potent RSK inhibitors.

Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.

Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.

In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.

Parametric numerical study of the modulation transfer function in small-pitch InGaAs/InP infrared arrays with refractive microlenses.

We report on the modulation transfer function (MTF) in short-wave infrared indium gallium arsenide (InGaAs) on indium phosphide (InP) planar photodetector arrays. Our two-dimensional numerical method consists of optical simulations using the finite-difference time domain method and drift-diffusion simulations using the finite-element method. This parametric study investigates MTF dependence on pitch, the addition of refractive microlenses, the thickness of the InGaAs absorber, and the doping concentration of the InGaAs absorber.

Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.

The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria.

Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors.

A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAF. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.

Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers.

RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify.

Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design.

The discovery of a highly potent and selective small molecule inhibitor 9 for in vitro target validation of MNK1/2 kinases is described. The aminopyrazine benzimidazole series was derived from an HTS hit and optimized by utilization of a docking model, conformation analysis, and binding pocket comparison against antitargets.

Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma.

Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.

Discovery of Potent and Selective RSK Inhibitors as Biological Probes.

While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the inhibition of YB1 phosphorylation.

Description of a new species of the Miniopterus aelleni group (Chiroptera: Miniopteridae) from upland areas of central and northern Madagascar.

Recent molecular genetic work, combined with morphological comparisons, on Malagasy members of the bat genus Miniopterus (Family Miniopteridae), has uncovered a number of cryptic species. Based on recently collected specimens and associated tissues, we examine patterns of variation in M. aelleni, the holotype of which comes from Ankarana in northern Madagascar.

Erratum to: Oxytocin enhances the appropriate use of human social cues by the domestic dog (Canis familiaris) in an object choice task.

Erratum to: Anim Cogn (2015) 18:767–775 DOI 10.1007/s10071-015-0843-7. Unfortunately, in the original publication the word ‘receptor’ under the sub-heading ‘The effect of gender on the efficacy of oxytocin’ has been incorrectly published as ‘peptide’.

Oxytocin enhances the appropriate use of human social cues by the domestic dog (Canis familiaris) in an object choice task.

It has been postulated that the neuropeptide, oxytocin, is involved in human-dog bonding. This may explain why dogs, compared to wolves, are such good performers on object choice tasks, which test their ability to attend to, and use, human social cues in order to find hidden food treats. The objective of this study was to investigate the effect of intranasal oxytocin administration, which is known to increase social cognition in humans, on domestic dogs' ability to perform such a task.

Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1.

Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity.

A structural portrait of the PDZ domain family.

PDZ (PSD-95/Discs-large/ZO1) domains are interaction modules that typically bind to specific C-terminal sequences of partner proteins and assemble signaling complexes in multicellular organisms. We have analyzed the existing database of PDZ domain structures in the context of a specificity tree based on binding specificities defined by peptide-phage binding selections. We have identified 16 structures of PDZ domains in complex with high-affinity ligands and have elucidated four additional structures to assemble a structural database that covers most of the branches of the PDZ specificity tree.